Pharmacokinetic Modeling and Dose Selection in a Randomized, Double-Blind, Placebo-Controlled Trial of a Human Recombinant Alkaline Phosphatase in Healthy Volunteers

Abstract

Background and ObjectivePrevious clinical trials have suggested that bovine intestinal alkaline phosphatase has renal protective effects in patients with sepsis-associated acute kidney injury. We conducted a first-in-human study to investigate the pharmacokinetics, safety and tolerability of a novel human recombinant alkaline phosphatase (recAP), and we developed a population pharmacokinetic model to support dose selection for future patient studies.MethodsIn a randomized, double-blind, placebo-controlled, phase I trial, healthy volunteers received a single dose of recAP (200, 500, 1000 or 2000 U/kg; n = 33; 3:1 ratio) or multiple doses of recAP (500 or 1000 U/kg; n = 18; 2:1 ratio) via a 1-h intravenous infusion on three consecutive days. Serum recAP concentrations, alkaline phosphatase (AP) activity levels and anti-drug antibodies were measured, and safety parameters were monitored. A population pharmacokinetic model was developed, and simulations were performed to guide dose selection for a phase IIa/b trial.ResultsPeak concentrations of recAP and peak AP activity were reached at the end of the 1-h infusion and showed a rapid decline, with about 10 % of the maximum concentration remaining at 4 h and less than 5 % remaining 24 h post-start. RecAP treatment was generally well tolerated, and anti-drug antibodies could not be detected in the serum up to 2 weeks post-injection after a single dose, or up to 3 weeks post-injection after multiple doses. A four-compartment model best described the pharmacokinetics of recAP administration, with moderate inter-individual variability on the central volume of distribution and elimination rate constant. Simulations showed that 1-h intravenous infusions of 250, 500 and 1000 U/kg recAP once every 24 h for three consecutive days constituted the dosing regimen that best met the criteria for dose selection in patient studies.ConclusionRecAP did not raise any safety concerns when administered to healthy volunteers. A population pharmacokinetic model was developed to support dose selection for patient studies.Trial Registration2013-002694-21 (EudraCT).Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0399-y) contains supplementary material, which is available to authorized users.

Study protocol for a multicentre randomised controlled trial:Safety,Tolerability, efficacy and quality of lifeOf a human recombinant alkalinePhosphatase in patients with sepsis-associatedAcuteKidneyInjury (STOP-AKI)

“…Since the study drug will be prepared, double-checked and administered by trained hospital staff, and since the dose levels under study have not caused any SAEs in healthy volunteers, 15 the risks for potential hazardous or life-threatening events due to medication errors are considered to be minimal.…”

“…In healthy volunteers, the maximum administered single dose was 3.2 mg/kg (2000 U/kg) and this dose did not result in any SAEs. 15 As an example of a possible dose error (eg, administration of the highest study dose for a 100 kg person to a 50 kg person), 1-day administration of study drug still would not exceed the tested maximum dose in healthy volunteers.…”

“… 13 In line with preclinical and clinical studies using purified biAP, animal studies with recAP revealed potent anti-inflammatory activity preserving function 14 and histological integrity of the affected kidneys (unpublished data) and administration to healthy volunteers did not raise any safety concerns. 15 Therefore, therapeutic application of recAP is predicted to exert potent tissue protective and anti-inflammatory effects in patients with SA-AKI. In order to investigate this hypothesis, a randomised placebo-controlled phase II trial is being conducted with recAP in critically ill patients suffering from SA-AKI.…”

Sepsis associated acute kidney injury

“…In preclinical and small clinical studies, systemic administration of alkaline phosphatase has shown protection in SA-AKI 158159160. Alkaline phosphatase has been thought to be effective through the direct dephosphorylation of endotoxin leading to attenuated inflammation and organ dysfunction and improved survival rates.…”

Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD

“…A phase I study showed that intravenous administration of a novel recombinant form of human IALP in healthy volunteers was safe and well tolerated 191 . Further clinical studies are needed to elucidate whether IALP could prevent and combat systemic and intestinal inflammation, metabolic syndrome and gut dysbiosis.…”